AAO: Anti-VEGF Drugs Making Leap to Diabetic Eye Disease

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Explain to interested patients that preliminary data from several recent studies indicates that medications approved for "wet" age-related macular degeneration also appeared to be effective in diabetic macular edema.

CHICAGO -- Drugs approved for "wet" age-related macular degeneration also appeared to be effective in diabetic macular edema in several clinical studies, researchers said here.

Ranibizumab (Lucentis) and pegaptanib (Macugen), both of which inhibit vascular endothelial growth factor (VEGF) signalling, were highly effective in improving visual acuity in patients with this form of diabetic retinopathy in a series of randomized, controlled trials, according to reports at the American Academy of Ophthalmology's annual meeting.

Results from the READ-2 and RESTORE trials, as well as another in a string from the Diabetic Retinopathy Clinical Research Network (DRCR.net) all indicated that ranibizumab -- whether or not added to laser therapy, and whether or not the laser treatment was prompt or delayed -- was more effective than laser therapy alone or intravitreal steroids.

The reports were featured here at a special session on retinal diseases, attended by more than 3,000 AAO meeting-goers.

Because neovascularization helps drive diabetic macular edema, both drugs -- as well as bevacizumab (Avastin), another VEGF inhibitor -- are often used off-label to treat retinopathy in diabetics. However, that has created a need for studies to confirm the drugs' benefits and safety in this application and to find the optimal doses and schedules.

Session discussant Lloyd Aiello, MD, PhD, of Joslin Diabetes Center in Boston, said that anti-VEGF treatments appear to be a real clinical option for patients with diabetic retinopathy.

But he cautioned that there is more that clinicians will want to know about these agents, and that they are not panaceas.

Aiello noted that optimal dosing schedules still need to be worked out and the identification of patient subgroups most likely to benefit (or not) has not been completed.

He also suggested that longer-acting agents would be welcomed, as all the studies indicated that treatment effects tend to wear off within a few weeks after each injection.

READ-2

Quan Dong Nguyen, MD, of Johns Hopkins University in Baltimore, presented two-year results from the READ-2 trial of ranibizumab compared with focal laser therapy and a combination of both treatments.

Patients in the trial received their assigned treatments on a rigid schedule for the first six months, at which point the two ranibizumab groups were clearly outperforming those receiving laser-only therapy.

All patients, including those initially assigned to laser therapy only, could then receive ranibizumab "as needed" according to clinicians' judgment for the remaining 18 months. Those in the combination group could also receive laser treatments during the follow-up period.

With 101 patients in the three arms evaluable after two years (about 20% of the original enrollment in each group were lost to follow-up), all three groups showed additional gains in visual acuity from months six to 24, ranging from 5.1 to 7.7 additional letters beyond their capabilities at month six.

He noted that a READ-3 study, designed to test different doses of ranibizumab (a single 0.5-mg dosage was evaluated in READ-2), had just completed its enrollment. The new study will also measure changes in retinal thickness to examine more directly the effect on macular edema.

RESTORE

Another randomized trial of ranibizumab was RESTORE, reported here by Ursula Schmidt-Erfurth, MD, of the Medical University of Vienna, in Austria.

Whereas READ-2 was open-label, RESTORE used sham treatments to provide blinded comparisons of ranibizumab, laser treatment, and the combination in 345 diabetic macular edema patients over one year.

As in the six-month READ-2 data, laser therapy alone did not improve visual acuity, with a mean increase of 0.8 letters in best-corrected acuity relative to baseline after one year.

Ranibizumab monotherapy and the combination led to mean increases of 6.1 and 5.9 letters, respectively, both with P values of less than 0.0001 relative to laser monotherapy.

Roughly 40% of both ranibizumab groups gained at least 10 letters in best-corrected acuity, compared with 16% of the laser monotherapy group. Notably, Schmidt-Erfurth reported, nearly as many patients in the laser-only group lost 10 letters of acuity, whereas less than 5% of the ranibizumab groups showed that much loss in acuity (P not given).

Adverse events were nearly identical in all three groups, she said.

Perhaps the most noteworthy finding, Schmidt-Ermurth added, was the similar efficacy in the two ranibizumab arms -- suggesting that the laser therapy "did not add further benefit."

DRCR.net Study

Much of the data had been published earlier this year, but Raj K. Maturi, MD, of Indiana University in Indianapolis, reviewed them for attendees, along with some findings from more recent analyses.

The multicenter study randomized a total of 854 eyes in 691 diabetic patients with visual acuity of 20/32 to 20/320 and diabetic macular edema involving the fovea to receive double-blind treatment with one of several regimens:

Prompt laser with sham intravitreal injections as a control group

Intravitreal ranibizumab (0.5 mg) plus laser treatment within three to 10 days after injection

Maturi discussed the two-year results. The main finding was that outcomes after one year were largely maintained in the second year with a relatively small number of retreatments.

At the two-year evaluation, about half of patients in both ranibizumab groups had gained 10 letters of visual acuity. Central subfield retinal thickness was normalized in the same proportion -- similar to results in the RESTORE and READ-2 trials.

Rates of elevated intraocular pressure were fairly low in the ranibizumab groups, Maturi said, affecting about 11% of eyes in these groups. Intraocular pressure increased in 7% of the sham-plus-laser group and 50% of those receiving triamcinolone.

The triamcinolone group also required cataract surgery at much higher rates (59% versus 14% for the other three groups).

Flexible retreatment

Susan Bressler, MD, of Johns Hopkins University, also reviewed the DRCR.net data to emphasize the importance of the flexible treatment regimen used in the study's second year.

The algorithm for retreatment appeared complicated but was based on what Bressler called "simple principles" -- to allow patients who would likely benefit from additional treatment to receive it, without subjecting other patients to unneeded or ineffective procedures.

Thus, during year two of the study, patients were evaluated for possible retreatment every four weeks. Those meeting prespecified "success" criteria -- best-corrected acuity of at least 84 letters plus normal central field thickness -- were sent home without additional treatment.

Also not retreated were patients who met criteria for treatment failure or futility, generally defined as worsening condition or lack of success and no improvement with previous treatments.

Bressler noted that the median number of retreatments provided during year two ranged from two to three in all the study arms, out of a possible 13 -- indicating that the algorithm successfully provided the desired flexibility.

She said that technology was a key element in making the algorithm work. Clinicians at the study sites worked with an electronic records system that had the algorithm parameters built in. Therefore, when clinicians entered results from an evaluation, the system prompted them with what they should do for that patient under the specified retreatment scheme.

Pegaptanib

A late addition to the program was a presentation by Marla Sultan, MD, MBA, of Pfizer, who presented results from a placebo-controlled phase II/III study of intravitreal pegaptanib in 288 macular edema patients.

After one year, 36.8% of patients in the pegaptanib arm met the study's primary endpoint, a 10-letter gain in acuity, compared with 19.7% of the placebo group (P=0.005).

Patients stayed in the trial for a second year. Sultan's data indicated that the first-year results were maintained in both groups. The mean improvement from baseline after two years was 6.1 letters in the pegaptanib arm (5.2 at one year), versus 1.3 letters in the placebo group at year two (1.2 letters at one year).

Adverse effects were uncommon and similar in both arms, she said, except for elevations in intraocular pressure immediately after injection. This was seen in 17 pegaptanib patients versus seven in the placebo group.

Ranibizumab in READ-2, RESTORE, and the DRCR.net study was supplied by Genentech. Pfizer sponsored the pegaptanib study.

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